Steven Teitelbaum

..Our studies have investigated whether absence of the alphavbeta3 integrin modifies the ability of c-Fms to induce Rho GTPases, and the implications for formation of the osteoclast cytoskeleton...

..In this issue of Cell Stem Cell, Wu et al. (2010) demonstrate that this event is mediated by osteoclastic mobilization of active transforming growth factor β1, which is inhibited by a common antiosteoporosis drug...

..Absence of any component of this signaling pathway compromises osteoclast cytoskeletal organization and abridges bone resorption...

..This review focuses on these and other molecules that mediate osteoclast differentiation or function and thus serve as candidate anti-osteoporosis therapeutic targets...

..In this issue of Cell, Lee et al. (2007) demonstrate in mice that bone regulates the insulin/glucose axis and energy metabolism, providing a new framework for approaching common disorders of bioenergetics...

..Achieving an understanding of the mechanisms by which the three cytokines affect the osteoclast has resulted in a number of active and candidate therapeutic targets...

..M-CSF and its receptor, c-Fms, therefore present as candidate therapeutic targets in states of inflammatory bone erosion...

..Thus, ritonavir may represent a bone-sparing PI capable of preventing development of osteopenia in patients currently on HAART...

..Thus, IL-1 mediates the osteoclastogenic effect of TNF by enhancing stromal cell expression of RANKL and directly stimulating differentiation of osteoclast precursors...

....

..Furthermore, the same cells plated onto osteopontin, adhere poorly and fail to phosphorylate c-Src or Pyk2, two kinases central to organization of the osteoclast cytoskeleton...

..Using a lentiviral-based strategy to express beta3 mutants in beta3(-/-) mice, we also show that beta3(S752), but not beta3(Y747/Y759), is important for osteoclastic bone resorption in vivo...

..FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling...

..Thus, unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption...

....

..Thus, we have identified specific tyrosine residues in the cytoplasmic tail of c-Fms that are critical for transmitting M-CSF-initiated signals individually required for OC formation or function, respectively...

..Thus, while c-Fms and alpha(v)beta(3) collaborate in the osteoclastogenic process via shared activation of the ERK/c-Fos signaling pathway, the integrin is essential for matrix degradation...

..Thus, NF-kappaB appears to be the centerpiece of inflammatory-osteolytic arthritis and direct inhibition of this transcription factor by unique and novel I-kappaB mutant proteins blocks manifestation of the disease...

..These data suggest that Cdc42 regulates osteoclast formation and function and may represent a promising therapeutic target for prevention of pathological bone loss...

..Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis...

..Together, our findings suggest that MAGP1 is a regulator of bone remodeling, and its absence results in osteopenia associated with an increase in osteoclast number...

..Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy...

..The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine...

..Thus, the beta3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function...

..These observations raise caution that therapeutic inhibition of NOTCH signaling may adversely accelerate bone loss in humans...

..In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled...

..Therefore, synaptotagmin VII plays an important role in bone remodeling and homeostasis by modulating secretory pathways functionally important in osteoclasts and osteoblasts...

..Furthermore, this same add-back approach identifies important roles for Tyr-697 and Tyr-721 in collaborating with Tyr-559 to recruit a multimeric signaling complex that can transduce signals from c-Fms to the actin cytoskeleton...

..Therefore, the bone-forming capacity of osteoblasts is distinct from their ability to maintain hematopoietic stem cells in chronic inflammatory conditions...

..Integrin/bone recognition also promotes formation of actin rings, which surround the ruffled border, thereby isolating the focus of skeletal degradation from the general extracellular space...

..We proposed that radiolabeled RGD peptides could be used to detect osteoclasts in lytic bone lesions...

..These data demonstrate a novel, biologically relevant means of regulating NF-kappaB signaling, with upstream control and kinetics distinct from the classical IkappaBalpha pathway...

..Signals from alphavbeta3 and/or c-Fms activate Syk and Vav3, originally defined by their function in lymphoid cells. Genetic depletion of either protein generates a strong bone phenotype, underscoring the promise of osteoimmunobiology...

..The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis...

..Finally, c-Fms-activated Syk also exerts its OC cytoskeleton-organizing effect in a SLP-76/Vav3-dependent manner...

..These counterbalancing events yield indistinguishable bones of WT and SLAP-/- mice which contain equal numbers of osteoclasts in basal and stimulated conditions...

..Our data provide genetic and biochemical evidence that uncovers an epistatic signaling pathway linking the receptor tyrosine kinase c-Fms to the immune adaptor DAP12 and the cytoskeleton...

..Consequently, Syk(Y317F) abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/Syk(Y317) association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis...

..The most pragmatic aspect of our findings is that successful therapeutic inhibition of c-Src, in the context of the osteoclast, will require its stringent targeting...

..Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and alpha v beta3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target...

..Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway...

..Using specific small molecule inhibitors we find that a combination of the Src family kinase, phosphatidylinositol 3-kinase/Akt, phospholipase C, and ERK pathways mediates macrophage proliferation in response to M-CSF...

..These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress...

..Thus, PMMA particle activation of NF-kappaB is a secondary event resulting from enhanced TNF expression and is independent of LPS contamination...

..Consequently, pathologically or pharmacologically inhibited resorption eventuates in arrested osteoblast activity...

..Hurchla, M. A., Deng, H., Floyd, D., Berdy, A., Prior, J. L., Piwnica-Worms, D., Teitelbaum, S. L., Ross, F. P., Weilbaecher, K. N. Dissection of platelet and myeloid cell defects by conditional targeting of the beta3-integrin subunit...

..Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GRoc-/- mice are protected from the steroid's inhibition of bone formation...

....

..Considering the widespread use of bisphosphonates, it appears that the overall risk of cortical fractures is low. However, there may be a subset of as yet unidentified patients who could be predisposed to this complication...

..Thus, SytVII-deficient mice experience suppressed bone resorption and formation with the latter deficiency predominant thereby yielding osteoporosis characterized by attenuated remodeling...

..Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation...

..Collectively, our data suggest that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption...

..These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation...

..abstract_text> ..

....

..abstract_text> ..

..We propose to identify the mechanisms by which these two proteins control bone mass, with the view of generating novel drugs to treat diseases such as osteoporosis. ..

..abstract_text> ..

..Information garnered from the supplemental Specific Aim may add to our armamentarium of potential anti-bone resorption therapeutic targets. ..

..The purpose of this proposal is to gain insight into the mechanism by which RANKL activates osteoclasts and to design candidate drugs which will inhibit this event and consequently, prevent pathological bone loss. ..

..We propose to identify the mechanisms by which these two proteins control bone mass, with the view of generating novel drugs to treat diseases such as osteoporosis. ..

....

..abstract_text> ..

..abstract_text> ..